A. Fatigue of single frog muscle fibers appeared as a decline in tension output during prolonged tetanic stimulation. The concentration of ATP (energy source for contraction) remained normal in fatigued fibers. Furthermore, ATP was not sequestered or unavailable for contraction. Fatigue therefore was due to an inability of the muscle to use energy in the form of ATP. We suggest that H ion, as lactic acid, accumulated in these fibers so as to interfere with excitation-contraction coupling. B. The perineurial sheath which surrounds peripheral axons may regulate nerve function and development. The permeability of the sheath of the frog sciatic nerve is very low to water-soluble nonelectrolytes and to ions, but can be increased by stretch or osmotic treatment. Ionic diffusion takes place through cells and intercellular tight junctions, but is not an active process. Following sectioning of the frog sciatic nerve, the perineurium undergoes a gradual increase in its permeability to 22Na during Wallerian degeneration with a time course that corresponds to the decline in the amplitude of the compound action potential. This indicates that perineurial integrity depends on functional integrity of the nerve.